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PURPOSE: Obsessive-compulsive disorder (OCD) and autism are characterized by the presence of repetitive behaviors. Differentiating between repetitive behaviors attributable to a diagnosis of autism, and those attributable to OCD, poses challenges for differential and co-occurring diagnosis. Differentiation is important to inform appropriate supports and interventions for phenotypically similar but functionally distinct behaviors. In this systematic review, the quantitative literature was examined to explore the similarities and differences in repetitive behaviors (including restricted and repetitive behaviors and interests, and obsessive-compulsive behaviors) in autistic individuals and those with OCD, and those with co-occurring diagnoses, in terms of: (1) expression, (2) content, and (3) associated factors. METHODS: Thirty-one studies were identified that compared repetitive behaviors in autistic individuals, individuals with OCD, or individuals with both diagnoses. RESULTS: The results suggest considerable overlap in the intensity and content of repetitive behaviors between groups. The findings of this review highlight that research aimed specifically at understanding similarities and differences in repetitive behaviors between autistic individuals and individuals with OCD is limited and frequently only compare at total score or composite measure levels. CONCLUSION: Further research into differences in the presentation of repetitive behaviors at a subscale and item level is required to inform clearer differentiation of specific behaviors in autism versus OCD. Understanding and more accurately differentiating is essential for efficient diagnosis, effective treatment, and better outcomes.
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There are epidemiological associations between obesity and type 2 diabetes, cardiovascular disease and Alzheimer's disease. The role of amyloid beta 42 (Aß42) in these diverse chronic diseases is obscure. Here we show that adipose tissue releases Aß42, which is increased from adipose tissue of male mice with obesity and is associated with higher plasma Aß42. Increasing circulating Aß42 levels in male mice without obesity has no effect on systemic glucose homeostasis but has obesity-like effects on the heart, including reduced cardiac glucose clearance and impaired cardiac function. The closely related Aß40 isoform does not have these same effects on the heart. Administration of an Aß-neutralising antibody prevents obesity-induced cardiac dysfunction and hypertrophy. Furthermore, Aß-neutralising antibody administration in established obesity prevents further deterioration of cardiac function. Multi-contrast transcriptomic analyses reveal that Aß42 impacts pathways of mitochondrial metabolism and exposure of cardiomyocytes to Aß42 inhibits mitochondrial complex I. These data reveal a role for systemic Aß42 in the development of cardiac disease in obesity and suggest that therapeutics designed for Alzheimer's disease could be effective in combating obesity-induced heart failure.
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Enfermedad de Alzheimer , Diabetes Mellitus Tipo 2 , Masculino , Ratones , Animales , Péptidos beta-Amiloides , Diabetes Mellitus Tipo 2/complicaciones , Anticuerpos Neutralizantes , Obesidad/complicaciones , Glucosa , Fragmentos de PéptidosRESUMEN
Cells create physical connections with the extracellular environment through adhesions. Nascent adhesions form at the leading edge of migrating cells and either undergo cycles of disassembly and reassembly, or elongate and stabilize at the end of actin fibers. How adhesions assemble has been addressed in several studies, but the exact role of actin fibers in the elongation and stabilization of nascent adhesions remains largely elusive. To address this question, here we extended our computational model of adhesion assembly by incorporating an actin fiber that locally promotes integrin activation. The model revealed that an actin fiber promotes adhesion stabilization and elongation. Actomyosin contractility from the fiber also promotes adhesion stabilization and elongation, by strengthening integrin-ligand interactions, but only up to a force threshold. Above this force threshold, most integrin-ligand bonds fail, and the adhesion disassembles. In the absence of contraction, actin fibers still support adhesions stabilization. Collectively, our results provide a picture in which myosin activity is dispensable for adhesion stabilization and elongation under an actin fiber, offering a framework for interpreting several previous experimental observations.
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Actinas , Integrinas , Integrinas/química , Ligandos , Actomiosina , Citoesqueleto de Actina , Adhesión Celular/fisiología , Adhesiones FocalesRESUMEN
This study explored the expression, occurrence, and treatment outcomes of comorbid body dysmorphic disorder (BDD) in 107 youth (7-17 years) seeking treatment for primary obsessive-compulsive disorder (OCD). In the overall sample, appearance anxiety (AA) was positively associated with OCD-related impairment, severity, symptom frequency, comorbid symptoms, and maladaptive emotion regulation. Comorbid BDD occurred in 9.35% of youth, equally affected males and females, and was associated with older age. AA negligibly reduced following treatment. Compared to those without (a) comorbid BDD and (b) without any comorbidity, youth with comorbid BDD reported greater social impairment and reduced global functioning but did not differ on the occurrence of comorbid anxiety and mood disorders. OCD response or remission rates did not differ. In youth with comorbid BDD, AA did not significantly reduce following treatment. Results suggest a more severe expression accompanies comorbid BDD in youth with OCD, with BDD persisting following OCD treatment.
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Trastorno Dismórfico Corporal , Trastorno Obsesivo Compulsivo , Masculino , Femenino , Adolescente , Humanos , Niño , Trastorno Dismórfico Corporal/epidemiología , Trastorno Dismórfico Corporal/terapia , Trastorno Obsesivo Compulsivo/epidemiología , Trastorno Obsesivo Compulsivo/terapia , Trastorno Obsesivo Compulsivo/diagnóstico , Trastornos de Ansiedad/epidemiología , Comorbilidad , AnsiedadRESUMEN
Short-chain enoyl-CoA hydratase 1 (ECHS1) is involved in the second step of mitochondrial fatty acid ß-oxidation (FAO), catalysing the hydration of short-chain enoyl-CoA esters to short-chain 3-hyroxyl-CoA esters. Genetic deficiency in ECHS1 (ECHS1D) is associated with a specific subset of Leigh Syndrome, a disease typically caused by defects in oxidative phosphorylation (OXPHOS). Here, we examined the molecular pathogenesis of ECHS1D using a CRISPR/Cas9 edited human cell 'knockout' model and fibroblasts from ECHS1D patients. Transcriptome analysis of ECHS1 'knockout' cells showed reductions in key mitochondrial pathways, including the tricarboxylic acid cycle, receptor-mediated mitophagy and nucleotide biosynthesis. Subsequent proteomic analyses confirmed these reductions and revealed additional defects in mitochondrial oxidoreductase activity and fatty acid ß-oxidation. Functional analysis of ECHS1 'knockout' cells showed reduced mitochondrial oxygen consumption rates when metabolising glucose or OXPHOS complex I-linked substrates, as well as decreased complex I and complex IV enzyme activities. ECHS1 'knockout' cells also exhibited decreased OXPHOS protein complex steady-state levels (complex I, complex III2 , complex IV, complex V and supercomplexes CIII2 /CIV and CI/CIII2 /CIV), which were associated with a defect in complex I assembly. Patient fibroblasts exhibit varied reduction of mature OXPHOS complex steady-state levels, with defects detected in CIII2 , CIV, CV and the CI/CIII2 /CIV supercomplex. Overall, these findings highlight the contribution of defective OXPHOS function, in particular complex I deficiency, to the molecular pathogenesis of ECHS1D.
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Proteínas Mitocondriales , Fosforilación Oxidativa , Humanos , Proteínas Mitocondriales/genética , Proteínas Mitocondriales/metabolismo , Proteómica , Enoil-CoA Hidratasa/genética , Enoil-CoA Hidratasa/metabolismo , Ácidos Grasos/metabolismoRESUMEN
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that stimulate mitochondrial biogenesis to boost ATP production. Here, we examined the effects of deoxyribonucleosides (dNs) on mitochondrial biogenesis and function in Short chain enoyl-CoA hydratase 1 (ECHS1) 'knockout' (KO) cells, which exhibit combined defects in both oxidative phosphorylation (OXPHOS) and mitochondrial fatty acid ß-oxidation (FAO). DNs treatment increased mitochondrial DNA (mtDNA) copy number and the expression of mtDNA-encoded transcripts in both CONTROL (CON) and ECHS1 KO cells. DNs treatment also altered global nuclear gene expression, with key gene sets including 'respiratory electron transport' and 'formation of ATP by chemiosmotic coupling' increased in both CON and ECHS1 KO cells. Genes involved in OXPHOS complex I biogenesis were also upregulated in both CON and ECHS1 KO cells following dNs treatment, with a corresponding increase in the steady-state levels of holocomplex I in ECHS1 KO cells. Steady-state levels of OXPHOS complex V, and the CIII2/CIV and CI/CIII2/CIV supercomplexes, were also increased by dNs treatment in ECHS1 KO cells. Importantly, treatment with dNs increased both basal and maximal mitochondrial oxygen consumption in ECHS1 KO cells when metabolizing either glucose or the fatty acid palmitoyl-L-carnitine. These findings highlight the ability of dNs to improve overall mitochondrial respiratory function, via the stimulation mitochondrial biogenesis, in the face of combined defects in OXPHOS and FAO due to ECHS1 deficiency.
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Enoil-CoA Hidratasa , Biogénesis de Organelos , Enoil-CoA Hidratasa/genética , Enoil-CoA Hidratasa/metabolismo , ADN Mitocondrial/genética , Ácidos Grasos/metabolismo , Glucosa , Carnitina , Desoxirribonucleósidos , Adenosina TrifosfatoRESUMEN
Near-term acute hypoxia in utero can result in significant fetal brain injury, with some brain regions more vulnerable than others. As mitochondrial dysfunction is an underlying feature of the injury cascade following hypoxia, this study is aimed at characterizing mitochondrial function at a region-specific level in the near-term fetal brain after a period of acute hypoxia. We hypothesized that regional differences in mitochondrial function would be evident, and that prophylactic creatine treatment would mitigate mitochondrial dysfunction following hypoxia; thereby reducing fetal brain injury. Pregnant Border-Leicester/Merino ewes with singleton fetuses were surgically instrumented at 118 days of gestation (dGa; term is ~145 dGA). A continuous infusion of either creatine (n = 15; 6 mg/kg/h) or isovolumetric saline (n = 16; 1.5 ml/kg/h) was administered to the fetuses from 121 dGa. After 10 days of infusion, a subset of fetuses (8 saline-, 7 creatine-treated) were subjected to 10 minutes of umbilical cord occlusion (UCO) to induce a mild global fetal hypoxia. At 72 hours after UCO, the fetal brain was collected for high-resolution mitochondrial respirometry and molecular and histological analyses. The results show that the transient UCO-induced acute hypoxia impaired mitochondrial function in the hippocampus and the periventricular white matter and increased the incidence of cell death in the hippocampus. Creatine treatment did not rectify the changes in mitochondrial respiration associated with hypoxia, but there was a negative relationship between cell death and creatine content following treatment. Irrespective of UCO, creatine increased the proportion of cytochrome c bound to the inner mitochondrial membrane, upregulated the mRNA expression of the antiapoptotic gene Bcl2, and of PCG1-α, a driver of mitogenesis, in the hippocampus. We conclude that creatine treatment prior to brief, acute hypoxia does not fundamentally modify mitochondrial respiratory function, but may improve mitochondrial structural integrity and potentially increase mitogenesis and activity of antiapoptotic pathways.
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Lesiones Encefálicas/etiología , Lesiones Encefálicas/metabolismo , Creatina/administración & dosificación , Hipoxia Fetal/complicaciones , Feto/metabolismo , Edad Gestacional , Hipocampo/metabolismo , Mitocondrias/metabolismo , Transducción de Señal/efectos de los fármacos , Animales , Apoptosis/efectos de los fármacos , Citocromos c/metabolismo , Modelos Animales de Enfermedad , Femenino , Mitocondrias/efectos de los fármacos , Membranas Mitocondriales/metabolismo , Embarazo , Proteínas Proto-Oncogénicas c-bcl-2/genética , Ovinos , Resultado del Tratamiento , Regulación hacia Arriba/efectos de los fármacos , Regulación hacia Arriba/genéticaRESUMEN
OBJECTIVE: To examine the efficacy of weight-adjusted D-cycloserine (DCS) (35 or 70 mg) relative to placebo augmentation of intensive exposure therapy for youth with obsessive-compulsive disorder (OCD) in a double-blind, randomised controlled trial, and examine whether antidepressant medication or patient age moderated outcomes. METHODS: Youth (n = 100, 7-17 years) with OCD were randomised in a 1:1 ratio to either DCS + exposure (n = 49) or placebo + exposure (n = 51). Assessments occurred posttreatment, 1 month later, and at 3 and 6 months. Pills were ingested immediately before sessions. RESULTS: Significant improvements on all outcomes were observed at posttreatment, and to 6-month follow-up. Treatment arms did not differ across time, with no significant time-by-medication interactions on symptom severity (T1 to T2 estimate: 9.3, 95% confidence interval [CI]: -11.2 to -7.4, and estimate -10.7, 95% CI: -12.6 to -8.7), diagnostic severity (T1 to T2 estimate: -2.0, 95% CI: -2.4 to -1.5 and estimate -2.5, 95% CI: -3.0 to -2.0) or global functioning (T1 to T2 estimate: 13.8, 95% CI: 10.6 to 17.0, and estimate 16.6, 95% CI: 13.2 to 19.9). Neither antidepressants at baseline nor age moderated primary outcomes. There were significantly fewer responders/remitters at 1- and 6-month follow-up among youth in the DCS condition stabilised on SSRIs, relative to youth not taking SSRIs. CONCLUSIONS: DCS augmented intensive exposure therapy did not result in overall additional benefits relative to placebo. Intensive exposure proved effective in reducing symptoms for the overall sample.
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Terapia Cognitivo-Conductual , Trastorno Obsesivo Compulsivo , Adolescente , Antidepresivos/uso terapéutico , Niño , Terapia Combinada , Cicloserina/uso terapéutico , Humanos , Trastorno Obsesivo Compulsivo/tratamiento farmacológico , Resultado del TratamientoRESUMEN
Objective: The current study utilized a single case series, non-concurrent multiple baseline design to examine the efficacy of training parents via telehealth videoconferencing in exposure and response prevention (ERP) for home delivery of the treatment for their children and adolescents with obsessive compulsive disorder (OCD). Method: There were nine participants aged 8 to 14 years who had received a primary diagnosis of OCD. The design involved a series of AB replications, whereby following pre-treatment assessments participants were randomly assigned to either a 2-week (n = 4) or 3-week (n = 5) baseline condition with weekly monitoring of their child's OCD symptoms. Following baseline, parents participated four weekly telehealth parent-training modules in delivering FAST (Families Accessing Skills Training) cognitive behavior therapy (CBT) with ERP (CBT-ERP) to children with OCD via videoconferencing with the clinician. Primary outcome measures were OCD symptom severity, diagnostic severity, and global functioning, which were assessed post-treatment and at 2 month follow-up. Results: The stability of the baseline period from pre-treatment to week 2 (for the 2-week condition) or to week 3 (for the 3-week condition) was established as there were no significant differences across baseline scores for parent target obsessions or parent target compulsions ratings. Significant improvements on the primary outcomes of clinician assessed symptom severity, diagnostic ratings, and global functioning were observed from baseline to post-treatment, and continued to 2 months follow-up. Conclusion: These data suggest that brief, parent training in FAST CBT-ERP via telehealth provides an overall effective intervention that is likely to be of most benefit to children and youth who are mild to moderate in severity.
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MicroRNA-101-3p (miR-101-3p) is a tumour suppressor that regulates cancer proliferation and apoptotic signalling. Loss of miR-101-3p increases the expression of the Polycomb Repressive Complex 2 (PRC2) subunit enhancer of zeste homolog 2 (EZH2), resulting in alterations to the epigenome and enhanced tumorigenesis. MiR-101-3p has also been shown to modulate various aspects of cellular metabolism, however little is known about the mechanisms involved. To investigate the metabolic pathways that are regulated by miR-101-3p, we performed transcriptome and functional analyses of osteosarcoma cells transfected with miR-101-3p. We found that miR-101-3p downregulates multiple mitochondrial processes, including oxidative phosphorylation, pyruvate metabolism, the citric acid cycle and phospholipid metabolism. We also found that miR-101-3p transfection disrupts the transcription of mitochondrial DNA (mtDNA) via the downregulation of the mitochondrial transcription initiation complex proteins TFB2M and Mic60. These alterations in transcript expression disrupt mitochondrial function, with significant decreases in both basal (54%) and maximal (67%) mitochondrial respiration rates. Native gel electrophoresis revealed that this diminished respiratory capacity was associated with reduced steady-state levels of mature succinate dehydrogenase (complex II), with a corresponding reduction of complex II enzymatic activity. Furthermore, miR-101-3p transfection reduced the expression of the SDHB subunit, with a concomitant disruption of the assembly of the SDHC subunit into mature complex II. Overall, we describe a new role for miR-101-3p as a modulator of mitochondrial metabolism via its regulation of multiple mitochondrial processes, including mtDNA transcription and complex II biogenesis.
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MicroARNs/metabolismo , Mitocondrias/metabolismo , Succinato Deshidrogenasa/metabolismo , Proteínas Quinasas Activadas por AMP/metabolismo , Apoptosis , Línea Celular Tumoral , ADN Mitocondrial , Regulación hacia Abajo , Regulación Neoplásica de la Expresión Génica , Humanos , Redes y Vías Metabólicas , MicroARNs/genética , Neoplasias/metabolismo , Osteosarcoma , Transducción de Señal , Succinato Deshidrogenasa/genéticaRESUMEN
Sound is an essential source of information in many taxa and can notably be used by embryos to programme their phenotypes for postnatal environments. While underlying mechanisms are mostly unknown, there is growing evidence for the involvement of mitochondria-main source of cellular energy (i.e. ATP)-in developmental programming processes. Here, we tested whether prenatal sound programmes mitochondrial metabolism. In the arid-adapted zebra finch, prenatal exposure to 'heat-calls'-produced by parents incubating at high temperatures-adaptively alters nestling growth in the heat. We measured red blood cell mitochondrial function, in nestlings exposed prenatally to heat- or control-calls, and reared in contrasting thermal environments. Exposure to high temperatures always reduced mitochondrial ATP production efficiency. However, as expected to reduce heat production, prenatal exposure to heat-calls improved mitochondrial efficiency under mild heat conditions. In addition, when exposed to an acute heat-challenge, LEAK respiration was higher in heat-call nestlings, and mitochondrial efficiency low across temperatures. Consistent with its role in reducing oxidative damage, LEAK under extreme heat was also higher in fast growing nestlings. Our study therefore provides the first demonstration of mitochondrial acoustic sensitivity, and brings us closer to understanding the underpinning of acoustic developmental programming and avian strategies for heat adaptation.
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Pinzones , Efectos Tardíos de la Exposición Prenatal , Aclimatación , Acústica , Adenosina Trifosfato/metabolismo , Animales , Pinzones/fisiología , Calor , Mitocondrias/metabolismo , Efectos Tardíos de la Exposición Prenatal/metabolismo , TemperaturaRESUMEN
Glass structures of multicomponent oxide systems (CaO-Al2O3-SiO2) are studied using a simulated pulsed laser with molecular dynamics. The short- and intermediate-range order structures revealed a direct correlation between the transformation of Al(IV) to Al(V), regions of increased density following laser processing, inherent reduction in the average T-O-T (T = Al, Si) angle, and associated elongation of the T-O bonding distance. Variable laser pulse energies were simulated across calcium aluminosilicate glasses with high silica content (50-80%) to identify densification trends attributed to composition and laser energy. High-intensity pulsed laser effects on fictive temperature and shockwave promotion are discussed in detail for their role in glass densification. Laser-induced structural changes are found to be highly dependent on pulse energy and glass chemistry.
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For over 40 years, measurements of the nucleation rates in a large number of silicate glasses have indicated a breakdown in the Classical Nucleation Theory at temperatures below that of the peak nucleation rate. The data show that instead of steadily decreasing with decreasing temperature, the work of critical cluster formation enters a plateau and even starts to increase. Many explanations have been offered to explain this anomaly, but none have provided a satisfactory answer. We present an experimental approach to demonstrate explicitly for the example of a 5BaO â 8SiO2 glass that the anomaly is not a real phenomenon, but instead an artifact arising from an insufficient heating time at low temperatures. Heating times much longer than previously used at a temperature 50 K below the peak nucleation rate temperature give results that are consistent with the predictions of the Classical Nucleation Theory. These results raise the question of whether the claimed anomaly is also an artifact in other glasses.
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Biologists have long appreciated the critical role that energy turnover plays in understanding variation in performance and fitness among individuals. Whole-organism metabolic studies have provided key insights into fundamental ecological and evolutionary processes. However, constraints operating at subcellular levels, such as those operating within the mitochondria, can also play important roles in optimizing metabolism over different energetic demands and time scales. Herein, we explore how mitochondrial aerobic metabolism influences different aspects of organismal performance, such as through changing adenosine triphosphate (ATP) and reactive oxygen species (ROS) production. We consider how such insights have advanced our understanding of the mechanisms underpinning key ecological and evolutionary processes, from variation in life-history traits to adaptation to changing thermal conditions, and we highlight key areas for future research.
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Metabolismo Energético , Mitocondrias , Adaptación Fisiológica , Adenosina Trifosfato/metabolismo , Humanos , Especies Reactivas de Oxígeno/metabolismoRESUMEN
Nucleation is generally viewed as a structural fluctuation that passes a critical size to eventually become a stable emerging new phase. However, this concept leaves out many details, such as changes in cluster composition and competing pathways to the new phase. In this work, both experimental and computer modeling studies are used to understand the cluster composition and pathways. Monte Carlo and molecular dynamics approaches are used to analyze the thermodynamic and kinetic contributions to the nucleation landscape in barium silicate glasses. Experimental techniques examine the resulting polycrystals that form. Both the modeling and experimental data indicate that a silica rich core plays a dominant role in the nucleation process.
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Mitochondrial OXPHOS generates most of the energy required for cellular function. OXPHOS biogenesis requires the coordinated expression of the nuclear and mitochondrial genomes. This represents a unique challenge that highlights the importance of nuclear-mitochondrial genetic communication to cellular function. Here we investigated the transcriptomic and functional consequences of nuclear-mitochondrial genetic divergence in vitro and in vivo. We utilized xenomitochondrial cybrid cell lines containing nuclear DNA from the common laboratory mouse Mus musculus domesticus and mitochondrial DNA (mtDNA) from Mus musculus domesticus, or exogenous mtDNA from progressively divergent mouse species Mus spretus, Mus terricolor, Mus caroli and Mus pahari. These cybrids model a wide range of nuclear-mitochondrial genetic divergence that cannot be achieved with other research models. Furthermore, we used a xenomitochondrial mouse model generated in our laboratory that harbors wild-type, C57BL/6J Mus musculus domesticus nuclear DNA and homoplasmic mtDNA from Mus terricolor. RNA sequencing analysis of xenomitochondrial cybrids revealed an activation of interferon signaling pathways even in the absence of OXPHOS dysfunction or immune challenge. In contrast, xenomitochondrial mice displayed lower baseline interferon gene expression and an impairment in the interferon-dependent innate immune response upon immune challenge with herpes simplex virus, which resulted in decreased viral control. Our work demonstrates that nuclear-mitochondrial genetic divergence caused by the introduction of exogenous mtDNA can modulate the interferon immune response both in vitro and in vivo, even when OXPHOS function is not compromised. This work may lead to future insights into the role of mitochondrial genetic variation and the immune function in humans, as patients affected by mitochondrial disease are known to be more susceptible to immune challenges.
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Núcleo Celular/genética , ADN Mitocondrial , Interferones/inmunología , Mitocondrias/genética , Animales , Línea Celular , Femenino , Genotipo , Inmunidad Innata , Masculino , Ratones/clasificación , Ratones Endogámicos C57BL , Ratones Transgénicos , Fosforilación OxidativaRESUMEN
The lack of effective treatments for mitochondrial disease has seen the development of new approaches, including those that aim to stimulate mitochondrial biogenesis to boost ATP generation above a critical disease threshold. Here, we examine the effects of the peroxisome proliferator-activated receptor γ (PPARγ) activator pioglitazone (PioG), in combination with deoxyribonucleosides (dNs), on mitochondrial biogenesis in cybrid cells containing >90% of the m.3243A>G mutation associated with mitochondrial encephalopathy, lactic acidosis, and stroke-like episodes (MELAS). PioG + dNs combination treatment increased mtDNA copy number and mitochondrial mass in both control (CON) and m.3243A>G (MUT) cybrids, with no adverse effects on cell proliferation. PioG + dNs also increased mtDNA-encoded transcripts in CON cybrids, but had the opposite effect in MUT cybrids, reducing the already elevated transcript levels. Steady-state levels of mature oxidative phosphorylation (OXPHOS) protein complexes were increased by PioG + dNs treatment in CON cybrids, but were unchanged in MUT cybrids. However, treatment was able to significantly increase maximal mitochondrial oxygen consumption rates and cell respiratory control ratios in both CON and MUT cybrids. Overall, these findings highlight the ability of PioG + dNs to improve mitochondrial respiratory function in cybrid cells containing the m.3243A>G MELAS mutation, as well as their potential for development into novel therapies to treat mitochondrial disease.
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Desoxirribonucleósidos/farmacología , Células Híbridas/metabolismo , Síndrome MELAS/patología , Mitocondrias/metabolismo , Pioglitazona/farmacología , Línea Celular Tumoral , Respiración de la Célula/efectos de los fármacos , ADN Mitocondrial/genética , Dosificación de Gen , Humanos , Células Híbridas/efectos de los fármacos , Síndrome MELAS/genética , Mitocondrias/efectos de los fármacos , Mutación/genética , Fosforilación Oxidativa/efectos de los fármacos , ARN Mensajero/genética , ARN Mensajero/metabolismoRESUMEN
Mitochondria provide the main source of energy for eukaryotic cells, oxidizing fatty acids and sugars to generate ATP. Mitochondrial fatty acid ß-oxidation (FAO) and oxidative phosphorylation (OXPHOS) are two key pathways involved in this process. Disruption of FAO can cause human disease, with patients commonly presenting with liver failure, hypoketotic glycaemia and rhabdomyolysis. However, patients with deficiencies in the FAO enzyme short-chain enoyl-CoA hydratase 1 (ECHS1) are typically diagnosed with Leigh syndrome, a lethal form of subacute necrotizing encephalomyelopathy that is normally associated with OXPHOS dysfunction. Furthermore, some ECHS1-deficient patients also exhibit secondary OXPHOS defects. This sequela of FAO disorders has long been thought to be caused by the accumulation of inhibitory fatty acid intermediates. However, new evidence suggests that the mechanisms involved are more complex, and that disruption of OXPHOS protein complex biogenesis and/or stability is also involved. In this review, we examine the clinical, biochemical and genetic features of all ECHS1-deficient patients described to date. In particular, we consider the secondary OXPHOS defects associated with ECHS1 deficiency and discuss their possible contribution to disease pathogenesis.